Breakthroughs, and new crises, in the lab

As Gary Lynch's team starts piecing together the story of memory, his health prompts him to look into his own brain.

Lynch Lab sits between a toll road and the UC Irvine main campus, in an office park of indistinguishable low-rise, beige-on-beige stucco buildings. Neuroscientist Gary Lynch had moved his lab and office -- for a while, just a desk in a hallway -- numerous times during his Irvine career, often as the result of some feud or slight. He ended up in the office park largely because everybody -- including him -- concluded all parties would be better-served if there were physical distance between Lynch and his university peers.

The lab is at 101 Theory Drive, a developer's idea of a scientific street name that Lynch found presumptuous.

It is a mark of the difficulty of life sciences -- biology and its many descendants -- that to call something a theory is to honor, not slight it. Theory, evolutionary biologist P.Z. Myers has written, is what scientists aspire to. Lynch, for all of his bombast, was respectful of the intellectual protocols of his science.

"I would have called it Hypothesis Drive," he said.

The hypothesis is the fundamental organizing principle in scientific research. Its "if this, then that" structure underlies almost all scientific experiments. The work in Lynch's lab has been driven by a single overriding hypothesis Lynch first published in 1980.

Lynch proposed that the fundamental act by which a memory was encoded involved a nearly instantaneous physical restructuring of portions of brain cells, called neurons. That restructuring allowed neurons to be built into small networks. Each small network would be a memory, he thought.

Lynch's research focused on a particular area of the brain, a structure called the hippocampus, long thought to be involved in memory. Most neurons in the hippocampus have roughly triangular bodies. Slender fiber extensions called dendrites sprout from the top and bottom. The branches coming out of the top are called apical dendrites. Those coming from the bottom are called basal dendrites.

Also coming out of the bottom is a single larger extension called an axon. All along their lengths, the dendrites are marked by microscopic nubs called spines, thousands of them per dendrite. The axons of one neuron extend to meet the dendritic spines of other neurons. These dendrite-axon junctions are the synapses.

Lynch proposed that the dendritic spines at these junctions changed shape during a process known as long-term potentiation (LTP), which resulted in the strengthening of the bond between a dendrite and an axon. The remodeled dendrites, he said, were the base elements of memory.

Lynch acknowledged that the details of the biochemical interactions that caused the shape change were complex and not well-understood -- at the time he originally proposed it, in fact, not understood at all.

But the crux of the hypothesis was that human interaction with the environment -- a glimpse of blue ocean, the touch of a silk scarf -- resulted in an actual physical change in cells in the brain, and that those changes were the underpinning of memory.

Two notable properties of memory are its vast size and that it can be made in a moment, yet last essentially forever. Any attempt to describe the physical components of memory had to account for those properties.

There are about 100 billion neurons in the human brain. Each neuron has dozens of dendrites, and each dendrite has thousands of potential synapses. So the synapses offered immense storage capacity. But how could storage be so long-lasting? "For me it was really, really obvious it had to be structural, but beyond that, what could I tell you?" Lynch said.

Aside from the pure scientific achievement of understanding the proposed memory mechanism, the value to ordinary people has become more apparent almost every day since Lynch proposed it.

We are in the midst of a brain failure epidemic. Worldwide, it is estimated that by 2040, more than 100 million people will suffer some form of dementia. The physical mechanisms of memory break, and do so with frightening frequency. Lynch was fond of saying that you had no hope of fixing it if you hadn't first figured out how it was supposed to work.

To understand why it can take so long to figure out, imagine a vast pile of broken plates. A hypothesis is what someone, after surveying the pile, might say about putting the pieces back together.

If the hypothesis holds for a while, survives challenge and criticism, much of it improbably hostile, it might eventually come to some rough, general acceptance and be joined to other hypotheses to form something more far-reaching. Neuroscientists habitually use a particular word to categorize such a body of thought -- or collected wisdom -- in a part of their science. They don't, as a layperson might, refer to it as a theory. Instead, they call it a story.

Lynch was perilously close to believing he knew the story of human memory -- why it exists, how it works, how it fails.